THE BENEFITS OF PIPERINE HAVE BEEN PROVEN BY RESEARCH!

Piperine is an active alkaloid with a remarkable spectrum of therapeutic activities, such as antioxidant, anti-inflammatory, immunomodulatory, antiasthmatic, anticonvulsant, antimutagenic, antimycobacterial, antiamoebic, and anticancer activities. This article summarizes the current knowledge on piperine, which supports the chemopreventive potential of this dietary phytochemical. Many mechanisms have been implicated to understand the chemopreventive effects of piperine.

Piperine has been reported to inhibit the proliferation and survival of many types of cancer cells through its effects on the activation of apoptotic signaling and inhibition of cell cycle progression. Piperine is known to affect cancer cells in a variety of other ways, such as affecting redox homeostasis, inhibiting cancer stem cell (CSC) self-renewal, and modulating ER stress and autophagy. Piperine can modify the activities of many enzymes and transcription factors to inhibit invasion, metastasis, and angiogenesis. Piperine is a potent inhibitor of p-glycoprotein (P-gp) and significantly affects the drug metabolizing enzyme (DME) system. Due to its inhibitory effect on P-gp activity, piperine can reverse multidrug resistance (MDR) in cancer cells and acts as a bioavailability enhancer for many chemotherapeutic agents. In this article, we highlight the potential of piperine as a promising chemopreventive agent against cancer, and the knowledge we have gathered in this review can be applied in the strategic planning of future studies, including human studies on piperine.

Importance of Piperine in Food

Piperine (Figure 1)1) is the most important dietary alkaloid mainly found in the fruits and roots of Black Pepper and Long Pepper species of the Piperaceae family (Zheng et al., 2016 ). Black pepper, often called the “king of spices”, has been used in Indian medical systems to treat gastrointestinal and respiratory diseases (Gorgani et al., 2017). The characteristic pungency and pungent taste of pepper is due to its high piperine content.

Piperine has been used for many therapeutic purposes in the past and is expected to continue to do so in the future. Piperine is an important dietary phytochemical due to its presence in spicy foods and its pharmacological activities (anti-inflammatory, antimetastatic, anticancer, larvicidal, leishmanicidal, immunosuppressive, antimycobacterial and antiparasitic activities). , 2008 ; Lu et al., 2012 ; Sahi et al., 2012 ; Rafiq et al., 2015 ; Rodgers et al., 2016 ; Samuel et al., 2016 ; Philipova et al., 2017 ; Soutar et al.,2017 ).

Piperine was first isolated from pepper extracts by Hans Christian Ørsted in 1819 (Gorgani et al., 2017 ). Piperine, along with its isomers isopiperine, chavicine, and isochavicine, belongs to the alkaloid family (Gorgani et al., 2017). Alkaloids are a group of naturally occurring organic compounds that contain a ring structure and a central nitrogen atom. In general, the nitrogen atom is located inside a heterocyclic ring structure (Cordell, 1981). Alkaloids have long been used as a reservoir for drug discovery infrastructure, and some of these alkaloids have already been approved by the US Food and Drug Administration (FDA), such as camptothecin, a known topoisomerase I inhibitor, and vinblastine, which interacts with tubulin to induce mitotic catastrophe (Lu et al., 2012).

The preventive anticancer effects of piperine on several types of cancer-causing agents, such as 7,12-dimethylbenz(a)anthracene and benzo(a)pyrene, demonstrate its potential as a chemopreventive agent against cancer (Selvendiran et al., 2004; Vellaichamy et al., 2009). To better understand the mechanistic role of piperine in cancer chemoprevention, it is useful to know how cancer develops.

Piperine structure. Piperine is an alkaloid containing a heterocyclic ring structure and a central nitrogen atom. The nitrogen atom is located within the ring structure.

Piperine induces cell cycle arrest

The cell cycle is essential for maintaining the continuity of cell proliferation and for protecting proliferating cells from DNA damage. The main protein regulators of the cell cycle are cyclin-dependent kinases (CDKs), cyclins, and CDK inhibitors (CKIs). Cancer development is often associated with loss of cell cycle regulation (Collins et al., 1997; Feitelson et al., 2015). Many chemopreventive agents are known to modulate cell cycle progression as part of their chemopreventive mechanism (Meeran and Katiyar, 2008). Piperine is involved in the arrest of cancer cells at different phases of the cell cycle through the induction and inhibition of various protein regulators and checkpoints (Figure ​(Figure4).4). For example, piperine arrests SKMEL-28 melanoma cells and mouse B16F0 cells in the G1 phase through the inhibition of cyclin D1 and the induction of p21 (Fofaria et al., 2014). Piperine likely acts by inducing ROS-mediated DNA damage, as indicated by the phosphorylation of H2AX at Ser139. As a result of piperine-induced DNA damage, ataxia telangiectasia and rad3-related protein (ATR) and checkpoint kinase 1 (Chk1) are activated, leading to cell cycle arrest and subsequent apoptosis (Fofaria et al., 2014). Piperine has long been considered responsible for stimulating ROS generation in cancer cells. ROS-blocking agents such as tyrone have been shown to protect cancer cells from piperine-mediated cell cycle arrest and apoptosis (Fofaria et al., 2014). Piperine-induced ROS generation has been associated with apoptosis in B16F10 melanoma cells and HRT-18 human adenocarcinoma cancer cells (Yaffe et al., 2013). Piperine arrests HT-29 colon carcinoma cells in G1 phase by inhibiting cyclins D1 and D3 and their activating partners CDK4 and CDK6, as well as by inhibiting phosphorylation of retinoblastoma protein (pRb) and induction of p21 and p27 (Y. 2015). Piperine was found to arrest prostate cancer cells (including both androgen-dependent, PC3 and androgen-independent, LNCaP and DU145 cells) in the G0/G1 phase through the suppression of cyclins (cyclin D1 and cyclin A) and the activation of CDK inhibitors (p2 p27). However, the cell cycle arrest in PC3 was less pronounced than in LNCaP and DU145 cells due to the less pronounced induction of p21 and p27 in PC3 (Ouyang et al., 2013). In addition to G0/G1 arrest, piperine arrests osteosarcoma cells in the G2/M phase of the cell cycle through the inhibition of cyclin B1 and the enhanced phosphorylation of cyclin-dependent kinase-1 (CDK1) and checkpoint kinase 2 (Chk2) (Zhang et al., 2015). Piperine-induced cell cycle arrest in the G2/M phase can also be observed in HeLa and MCF-7 cells, and in this case, piperine-induced ROS generation is thought to be responsible for the induction of cell cycle arrest (Jain et al., 2016). Piperine may be useful in chemoprevention of TNBC and hormone-dependent breast cancer cells without affecting normal breast epithelial cell growth. Piperine blocks the growth and invasiveness of TNBC cells by inhibiting G1-associated (cyclin D3, CDK4, E2F-1) and G2-associated (cyclin B, CDK1, Cdc25C) proteins, as well as by inducing p21 (Greenshields et al., 2015). Notably, caspase activation, rather than ROS generation, is involved in piperine-induced cell death in TNBC cells. The inhibitory effect of piperine on cell cycle progression suggests that piperine may be a promising chemopreventive agent against cancer.

Piperine enhances drug bioavailability

Due to its inhibitory effect on P-gp activity, piperine acts as an effective bioavailability enhancer for a number of chemotherapeutic agents (Bhardwaj et al., 2002). Piperine is considered the world’s first scientifically proven bioavailability enhancer (Atal and Bedi, 2010). Various mechanisms have been proposed to explain the bioenhancing activity of piperine. For example, piperine inhibits P-gp and cytochrome P450 3A4 (CYP3A4), both of which contribute to the primary elimination of many drugs (Atal and Bedi, 2010). CYP3A4 alone metabolizes ~50% of marketed drugs (Zhou, 2008). Other DMEs affected by piperine include CYP1A1, CYP1B1, CYP1B2, CYP2E1, CYP3A4, etc. Thus, all drugs that are metabolized by these enzymes are affected by the administration of piperine, making piperine a non-specific enzyme system (Atal et al., 1985). Piperine is an inhibitor of UDP-glucuronosyltransferase (Singh et al., 1986). Piperine significantly enhanced the bioavailability of many chemopreventive agents such as resveratrol, mainly by inhibiting glucuronidation. Consequently, when resveratrol is administered together with piperine, the plasma concentration of resveratrol is significantly increased (Johnson et al., 2011).

Piperine enhances radiosensitization of tumors resistant to other diseases

Ionizing radiation (IR) has long been used in cancer therapy (Baskar et al., 2014). The goal of using IR in cancer treatment is to ensure that cancer cells are directly or at least rendered incapable of proliferation. However, toxicity to normal tissue and dose-limiting radioresistance of some tumors limit the clinical use of IR in cancer therapy (Kim et al., 2015). Many phytochemicals have been identified that can specifically lower the threshold of cancer cell death when used in conjunction with ionizing radiation. Such agents are known as radiosensitizers. A recent study showed that piperine can enhance the radiosensitivity of cancer cells without affecting the sensitivity of normal cells (Tak et al., 2012). Piperine has been shown to enhance IR-induced apoptosis in cancer cells, presumably by increasing ROS generation, leading to MMP dissipation and subsequent cell death (Tak et al., 2012). Piperine has also been reported to act as a potent ultraviolet (UV)-B photosensitizer in B16F10 murine melanoma cells (Rafiq et al., 2015). Therefore, when used in combination with UVB, piperine enhances intracellular ROS generation and disrupts intracellular calcium homeostasis, which, together with the attenuation of survival signaling pathways, leads to enhanced cell death in B16F10 cells.

Future Prospects

There are a large number of alkaloids that can prevent cancer development. Many natural alkaloids have been screened, identified and successfully converted into FDA-approved anticancer drugs. Chemoprevention using phytochemicals from fruits, vegetables and spices is an important preventive strategy against cancer development. Piperine has recently attracted much attention due to its chemopreventive properties. Piperine possesses potential chemopreventive properties, which may be due to induction cell cycle arrest, increased cell apoptosis, disruption of redox homeostasis, attenuation of CSC self-renewal, inhibition of angiogenesis, and modulation of stress. It should be noted that the hydrophobic nature and poor water solubility of piperine limit the clinical use of this natural molecule. The information we have gathered in this review has shown that piperine can specifically affect different types of cancer cells and exhibit specific mechanisms of action according to the type of cancer it affects. However, the exact mechanism of the chemopreventive effect of piperine on cancer development is not fully understood. Therefore, the exact mechanism of action of piperine needs to be confirmed before final recommendations can be made for the clinical use of this natural molecule. The hope is that piperine can be administered with minimal risk to humans and will produce a significant chemopreventive effect. The information we have gathered in this review has shown that piperine can specifically affect different types of cancer cells and exhibit specific mechanisms of action according to the type of cancer it affects. However, the exact mechanism of the chemopreventive effect of piperine on cancer development is not fully understood. Therefore, the exact mechanism of action of piperine needs to be confirmed before final recommendations can be made for the clinical use of this natural molecule. The hope is that piperine can be administered with minimal risk to humans, resulting in a significant chemopreventive effect. The information we have gathered in this review has shown that piperine can specifically affect different types of cancer cells and exhibit specific mechanisms of action according to the type of cancer it acts on. However, the exact mechanism of piperine's chemopreventive effect on cancer development is not fully understood. Therefore, the exact mechanism of piperine's action needs to be confirmed before definitive recommendations can be made for the clinical use of this natural molecule. The hope is that piperine can be administered with minimal risk to humans, resulting in a significant chemopreventive effect. The exact mechanism of piperine's chemopreventive effect on cancer development is not fully understood. Therefore, the exact mechanism of piperine's action needs to be confirmed before definitive recommendations can be made for the clinical use of this natural molecule. The hope is that piperine can be administered with minimal risk to humans, resulting in a significant chemopreventive effect. The exact mechanism of piperine's chemopreventive action on cancer development is not yet fully understood. Therefore, the exact mechanism of piperine's action must be confirmed before definitive recommendations can be made for the clinical use of this natural molecule. The hope is that piperine can be administered with minimal risk to humans, resulting in a significant chemopreventive effect.